Dofetilide

Dofetilide
Clinical data
Trade names	Tikosyn
AHFS/Drugs.com	Monograph
MedlinePlus	a601235
ATC code	C01BD04 (WHO) ;
Legal status
Legal status	US: WARNING;
Pharmacokinetic data
Bioavailability	96% (oral)
Protein binding	60% -70%
Elimination half-life	10 hours
Identifiers
	IUPAC name N-[4-(2-{[2-(4-methane sulfonamidophenoxy)ethyl] (methyl)amino}ethyl)phenyl]methanesulfonamide;
CAS Number	115256-11-6 ;
PubChem CID	71329;
IUPHAR/BPS	2604;
DrugBank	DB00204 ;
ChemSpider	64435 ;
UNII	R4Z9X1N2ND;
KEGG	D00647 ;
ChEBI	CHEBI:4681 ;
ChEMBL	ChEMBL473 ;
CompTox Dashboard (EPA)	DTXSID5046433 ;
ECHA InfoCard	100.166.441
Chemical and physical data
Formula	C19H27N3O5S2
Molar mass	441.56 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=S(=O)(Nc1ccc(cc1)CCN(CCOc2ccc(cc2)NS(=O)(=O)C)C)C;
	InChI InChI=1S/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3 ; Key:IXTMWRCNAAVVAI-UHFFFAOYSA-N ;
	(verify)

Dofetilide is a class III antiarrhythmic agent.^[2] It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 μg of dofetilide. It is not available in Europe^[3] or Australia.^[4]

Medical uses

Dofetilide is used for the maintenance of sinus rhythm in individuals prone to the occurrence of atrial fibrillation and flutter arrhythmias, and for chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.^[5]^[6]

Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide ("DIAMOND") study,^[7] dofetilide does not affect mortality in the treatment of patients post-myocardial infarction with left ventricular dysfunction, however it was shown to decrease all-cause readmissions as well as CHF-related readmissions.^[7] Because of the results of the DIAMOND study, some physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction, however use appears limited: After initially receiving marketing approval in Europe in 1999, Pfizer voluntarily withdrew this approval in 2004 for commercial reasons^[3] and it is not registered in other first world countries.

It has clinical advantages over other class III antiarrhythmics in chemical cardioversion of atrial fibrillation, and maintenance of sinus rhythm, and does not have the pulmonary or hepatotoxicity of amiodarone, however atrial fibrillation is not generally considered life-threatening, and dofetilide causes an increased rate of potentially life-threatening arrhythmias in comparison to other therapies.^[8]

Contraindications

Prior to administration of the first dose, the corrected QT (QTc) must be determined. If the QTc is greater than 440 msec (or 500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. If heart rate is less than 60 bpm, the uncorrected QT interval should be used. After each subsequent dose of dofetilide, QTc should be determined and dosing should be adjusted.

If at any time after the second dose of dofetilide the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued. ^[9]

Adverse effects

Torsades de pointes is the most serious side effect of dofetilide therapy. The incidence of torsades de pointes is 0.3-10.5% and is dose-related, with increased incidence associated with higher doses. The majority of episodes of torsades de pointes have occurred within the first three days of initial dosing. Patients should be hospitalized and monitored for the first three days after starting dofetilide.^[7]

The risk of inducing torsades de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial creatinine measurement, continuous telemetry monitoring and availability of cardiac resuscitation.

Pharmacology

Mechanism of action

Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (I_Kr).^[10]

This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter.

Dofetilide does not affect dV/dT_max (the slope of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.

There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.

Pharmacokinetics

Peak plasma concentrations are seen two to three hours after oral dosing when fasting. Dofetilide is well absorbed in its oral form, with a bioavailability of >90%. Intravenous administration of dofetilide is not available in the United States.^[11]

The elimination half-life of dofetilide is roughly 10 hours; however, this varies based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours. Due to the significant level of renal elimination (80% unchanged, 20% metabolites), the dose of dofetilide must be adjusted to prevent toxicity due to impaired renal function.^[12]

Dofetilide is metabolized predominantly by CYP3A4 enzymes predominantly in the liver and GI tract. This means that it is likely to interact with drugs that inhibit CYP3A4, such as erythromycin, clarithromycin, or ketoconazole, resulting in higher and potentially toxic levels of dofetilide.^[13]

Metabolism

A steady-state plasma level of dofetilide is achieved in 2–3 days.

80% of dofetilide is excreted by the kidneys, so the dose of dofetilide should be adjusted in individuals with chronic kidney disease, based on creatinine clearance.

In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamil, cimetidine, hydrochlorothiazide, itraconazole, ketoconazole, prochlorperazine, and trimethoprim should not be administered to individuals taking dofetilide.

About 20 percent of dofetilide is metabolized in the liver via the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4 isoenzyme system.

History

After its initial US FDA approval, due to the pro-arrhythmic potential, it was only made available to hospitals and prescribers that had received education and undergone specific training in the risks of treatment with dofetilide; however, this restriction was subsequently removed in 2016. ^[14]

References

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ Lenz TL, Hilleman DE (July 2000). "Dofetilide, a new class III antiarrhythmic agent". Pharmacotherapy. 20 (7): 776–786. doi:10.1592/phco.20.9.776.35208. PMID 10907968. S2CID 19897963.
^ ^a ^b Wathion N (2004-04-13). "Public Statement on Tikosyn (dofetilide): Voluntary Withdrawal of the Marketing Authorisation in the European Union" (PDF). European Agency for the Evaluation of Medicinal Products. Archived from the original (PDF) on 2017-10-13. Retrieved 2015-01-03.
^ Australian Medicines Handbook 2014
^ Banchs JE, Wolbrette DL, Samii SM, Penny-Peterson ED, Patel PP, Young SK, et al. (November 2008). "Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter". Journal of Interventional Cardiac Electrophysiology. 23 (2): 111–115. doi:10.1007/s10840-008-9290-6. PMID 18688699. S2CID 25162347.
^ Lenz TL, Hilleman DE (November 2000). "Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter". Drugs of Today. 36 (11): 759–771. doi:10.1358/dot.2000.36.11.601530. PMID 12845335.
^ ^a ^b ^c Torp-Pedersen C, Møller M, Bloch-Thomsen PE, Køber L, Sandøe E, Egstrup K, et al. (September 1999). "Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group". The New England Journal of Medicine. 341 (12): 857–865. doi:10.1056/NEJM199909163411201. PMID 10486417.
^ Micromedex Drugdex drug evaluations micromedex.com
^ "TIKOSYN® (dofetilide)". Pfizer.
^ Roukoz H, Saliba W (January 2007). "Dofetilide: a new class III antiarrhythmic agent". Expert Review of Cardiovascular Therapy. 5 (1): 9–19. doi:10.1586/14779072.5.1.9. PMID 17187453. S2CID 11255636.
^ Rasmussen HS, Allen MJ, Blackburn KJ, Butrous GS, Dalrymple HW (1992). "Dofetilide, a novel class III antiarrhythmic agent". Journal of Cardiovascular Pharmacology. 20 (Suppl 2): S96–105. doi:10.1097/00005344-199220002-00015. PMID 1279316.
^ "Dofetilide." Lexicomp. Wulters Kluwer Health, n.d. Web. <online.lexi.com>.
^ Walker DK, Alabaster CT, Congrave GS, Hargreaves MB, Hyland R, Jones BC, et al. (April 1996). "Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data". Drug Metabolism and Disposition. 24 (4): 447–455. PMID 8801060.
^ "Information for Tikosyn (dofetilide)". US Food and Drug Administration. 2016-03-09.